Biology subjects

Williams, L. M.

Publications and source records attributed to Williams, L. M..

14 recordsLinked to original sources

bioRxiv2026

Indole-3-propionic acid nano-prodrugs sustain increased lymphoid exposure and alleviate experimental autoimmune arthritis

Chronic inflammatory diseases, including rheumatoid arthritis (RA), currently require sustained control of inflammation. Although long-acting therapies can reduce dosing frequency, those that rely on systemic immunosuppression may still compromise protective immunity. Microbiota-derived metabolites offer a complementary starting point for immune modulation through naturally occurring host-microbe signals. Indole-3-propionic acid (IPA), a gut microbial tryptophan metabolite naturally present in human circulation, has newly recognized immunoregulatory activity, yet its effects across disease contexts and its potential for therapeutic use remain incompletely defined. Here, we developed polymeric IPA nano-prodrugs (pIPANP) by conjugating IPA to a methacrylamide polymer through ester linkages and formulating the polymer into injectable nanoparticles. Following subcutaneous administration of fluorescently-labeled pIPANP, injection-site fluorescence remained detectable for at least 35 days, with labeled material detected in multiple lymph nodes. LC-MS/MS confirmed higher lymph-node IPA concentrations in mice treated with the pIPANPs compared to free IPA control at every sampled time point over 14 days. In collagen antibody-induced arthritis (CAIA), pIPANPs reduced clinical disease severity and paw swelling under both prophylaxis and therapeutic administration. pIPANP treatment increased the relative representation of CD11cCD103CD11b- cells with a conventional dendritic cell (cDC)1-associated phenotype and reduced costimulatory-marker frequencies in both CD11cCD103 and CD11cCD11b populations, most prominently in hock-draining lymph nodes. These changes were accompanied by increased PD-1 and IFN-{gamma} frequencies among CD4 and CD8 T cells. Fluorescent nanoparticle tracking showed preferential association with several myeloid populations, while single-cell profiling revealed divergent interferon-response signatures across splenic populations. These findings reveal arthritis-associated immunomodulatory activity of polymeric IPA and support its further development as a microbiome-inspired, long-acting approach to inflammatory arthritis.

bioengineering↗

bioRxiv2026

HARMONY: A large-scale harmonized neuroimaging dataset for research on anxious misery disorders

Patterns of brain circuit dysfunction underlying depression and anxiety have been increasingly characterized, including dimensional and subtype variation. A key challenge is determining how such patterns generalize across populations and measurement frameworks. Here, we introduce HARMONY, a harmonized multimodal neuroimaging dataset supporting large-scale investigation of brain-behavior associations across symptom-defined dimensions. HARMONY integrates four Human Connectome Project-style Connectomes Related to Human Disease cohorts spanning adolescence to later adulthood and capturing anxious misery symptoms. The resource combines standardized HCP-style preprocessing, quality control, imaging-derived phenotypes, and harmonized symptom measures into a clinically enriched public dataset. Proof-of-concept analyses using HARMONY showed that pooling heterogeneous cohorts increased statistical power for detecting associations between imaging-derived phenotypes and anhedonia and depression severity. Effect sizes remained modest, consistent with symptom-based measures across heterogeneous samples. Functional imaging-derived phenotypes showed the strongest multivariate predictive performance. In summary, HARMONY provides a large multi-cohort resource for reproducible mental health neuroimaging research.

neuroscience↗

bioRxiv2025

Topological data analysis reveals rigid brain-state dynamics during self-viewing in trait rumination

Rumination--repetitive, negatively valenced, self-focused thought--is a maladaptive cognitive style linked to emotional dysregulation and psychiatric risk. To investigate its neural underpinnings in a naturalistic context, we developed an fMRI paradigm in which participants observed and reflected on videos of their own past group-based problem-solving sessions, a naturalistic self-relevant context rarely examined in fMRI studies. Thirty-two adults (mean age = 30.4 {+/-} 5.4 years; 13 F) were recorded during collaborative design-thinking tasks in triads. In a subsequent scanning session, each participant viewed two self-relevant team videos and one control team video, followed by a structured reflection period. We assessed trait rumination using the Rumination-Reflection Questionnaire (RRQ) and applied Topological Data Analysis (TDA) via the Mapper algorithm to model individual-level whole-brain dynamics during the task. Mapper shape graphs captured temporal transitions between brain states, allowing us to quantify the similarity of timepoints across the session. Individuals with higher trait rumination showed significantly higher temporal similarity, indicating reduced brain-state variability, during self-relevant conditions (r = 0.46, p = 0.018). This effect was not observed during the control condition. These findings suggest that rumination is associated with rigid brain dynamics during self-observation and evaluative processing. Traditional GLM and inter-subject correlation (ISC) analyses confirmed task engagement of key self-referential and social-evaluative regions, while Mapper revealed dynamic features not captured by static or group-averaged methods. Together, these findings demonstrate that trait rumination is associated with rigid large-scale brain dynamics during self-relevant cognition and highlight the value of combining naturalistic paradigms with topological approaches to capture behaviorally meaningful signatures. Significance StatementRumination--repetitive, self-focused thought--is a core cognitive feature of depression and anxiety. However, the neural dynamics underlying this mental inflexibility remain poorly understood, especially during ecologically valid, self-relevant experiences. Using topological data analysis and a naturalistic self-reflection fMRI paradigm, we identify a novel neural marker: individuals with higher rumination traits exhibit reduced flexibility in brain state transitions when watching videos of themselves. This signature is uniquely captured by Mapper, a data-driven geometric framework, and not detected by traditional neuroimaging methods. Our findings offer a new window into how maladaptive thought patterns manifest in brain dynamics, paving the way for personalized diagnostics and interventions in mood disorders.

neuroscience↗

bioRxiv2025

Comparison of Activities of Transcription Factor NF-κB from Two Jellyfish Models

Herein, transcription factor Nuclear Factor-kappaB (NF-{kappa}B) is characterized as the downstream effector of putative innate immune signaling pathways from two model jellyfish, Aurelia aurita (Aa) and Clytia hemisphaerica (Ch). Both jellyfish NF-{kappa}B proteins consist primarily of the N-terminal DNA-binding/dimerization domain, and they lack the C-terminal ankyrin repeat inhibitory domain found in vertebrate NF-{kappa}B proteins. Both jellyfish NF-{kappa}B proteins bind to a consensus mammalian NF-{kappa}B binding site, and their AlphaFold3-predicted structures on DNA are similar to that of mouse NF-{kappa}B p50. Neither Aa- nor Ch-NF-{kappa}B activated transcription of an NF-{kappa}B-site reporter gene in human cells; however, Aa-NF-{kappa}B did activate transcription from a GAL4-site reporter gene in yeast, whereas Ch-NF-{kappa}B did not. Aa- and Ch-NF-{kappa}B were both constitutively located in the nucleus when expressed in vertebrate cells. Homologs of I{kappa}B-like proteins from both species interacted with their corresponding NF-{kappa}B proteins in co-immunoprecipitation assays in HEK 293T cells. These I{kappa}B-like proteins influenced the subcellular localization of their cognate NF-{kappa}B proteins in vertebrate cells, and their ankyrin repeat domains were predicted to interact with Ch-NF-{kappa}B in a manner similar to mammalian I{kappa}B and NF-{kappa}B. RNA-sequencing data from Ch animals indicate that Ch-NF-{kappa}B is expressed at high levels in early developmental stages, when Ch-I{kappa}B expression is low, suggesting that active Ch-NF-{kappa}B controls an early developmental process. In contrast, in adult animals the expression of Ch-I{kappa}B is high, suggesting that Ch-NF-{kappa}B requires a signal in order to become active. Overall, these results provide comparative information on the structure, activity, and mRNA expression of jellyfish NF-{kappa}B pathway proteins among jellyfish, and they suggest roles for NF-{kappa}B in developing and adult jellyfish.

molecular biology↗

bioRxiv2023

A platform for standardized, online delivered, clinically applicable neurocognitive assessment: WebNeuro

We are in the midst of a paradigm shift in which we see a precision mental health and the emergence of brain-based assessments for personalizing treatments. The precision emphasis of precision mental health includes a focus on measurement. Within the biopsychosocial domains of measurement, objective measures of cognitive function have an important role in disorders of mental health. Here, data integrating the development, norming, validation, psychometric testing and clinical application of a web-delivered neurocognitive assessment (WebNeuro) are presented. WebNeuro is designed for low-burden assessment of 12 domains of general and emotional cognition within 35-40 minutes, remotely and via each participants own computer. Data are from 1,317 healthy participants and over 500 clinical participants across diagnoses. Results provide norms across nine decades, and demonstrate the construct validity, internal consistency, and test-retest reliability of WebNeuro. Findings also show that WebNeuro identifies neurocognitive impairments across multiple neuropsychiatric disorders.

neuroscience↗

bioRxiv2023

UNRAVELing the synergistic effects of psilocybin and environment on brain-wide immediate early gene expression in mice

The effects of context on the subjective experience of serotonergic psychedelics have not been fully examined in human neuroimaging studies, partly due to limitations of the imaging environment. Here, we administered saline or psilocybin to mice in their home cage or an enriched environment, immunofluorescently-labeled brain-wide c-Fos, and imaged cleared tissue with light sheet microscopy to examine the impact of context on psilocybin-elicited neural activity at cellular resolution. Voxel-wise analysis of c-Fos-immunofluorescence revealed differential neural activity, which we validated with c-Fos+ cell density measurements. Psilocybin increased c-Fos expression in the neocortex, caudoputamen, central amygdala, and parasubthalamic nucleus and decreased c-Fos in the hypothalamus, cortical amygdala, striatum, and pallidum. Main effects of context and psilocybin-treatment were robust, widespread, and spatially distinct, whereas interactions were surprisingly sparse.

neuroscience↗

bioRxiv2021

Attention enhances category representations across the brain with strengthened residual correlations to ventral temporal cortex

How does attention enhance neural representations of goal-relevant stimuli while suppressing representations of ignored stimuli across regions of the brain? While prior studies have shown that attention enhances visual responses, we lack a cohesive understanding of how selective attention modulates visual representations across the brain. Here, we used functional magnetic resonance imaging (fMRI) while participants performed a selective attention task on superimposed stimuli from multiple categories and used a data-driven approach to test how attention affects both decodability of category information and residual correlations (after regressing out stimulus-driven variance) with category-selective regions of ventral temporal cortex (VTC). Our data reveal three main findings. First, when two objects are simultaneously viewed, the category of the attended object can be decoded more readily than the category of the ignored object, with the greatest attentional enhancements observed in occipital and temporal lobes. Second, after accounting for the response to the stimulus, the correlation in the residual brain activity between a cortical region and a category-selective region of VTC was elevated when that regions preferred category was attended vs. ignored, and more so in the right occipital, parietal, and frontal cortices. Third, we found that the stronger the residual correlations between a given region of cortex and VTC, the better visual category information could be decoded from that region. These findings suggest that heightened residual correlations by selective attention may reflect the sharing of information between sensory regions and higher-order cortical regions to provide attentional enhancement of goal-relevant information.

neuroscience↗

bioRxiv2021

Acute Ketamine Modulated Functional Brain Coupling and Dissociative and Affective States in Human Subjects: Interim Analyses

Ketamine is a non-competitive antagonist of the N-methyl-D-aspartate (NMDA) glutamate receptor that is both a drug of abuse and an FDA-approved anesthetic used off-label for treatment-resistant depression. Despite its growing clinical use for depression and pain, the relationships between the acute dissociative and affective effects of ketamine that contribute to its abuse liability and therapeutic potential, along with the neural mechanisms underlying these effects, are not well established. To address this need, we have implemented a randomized, double-blinded, placebo-controlled, within-subjects mechanistic trial. Healthy adult subjects undergo infusion with two fixed doses of subanesthetic racemic intravenous (IV) ketamine and placebo and their acute responses are assessed with self-report questionnaires, behavioral measures, hormone levels, and neuroimaging. As planned in our analysis strategy, we present interim results for the first 7 subjects of our study, focusing on dissociative and affective states and resting functional brain coupling signatures of these states. The first key finding was that ketamine induced dose-dependent increases in dissociation and related intoxication. Ketamine also altered affective states, reducing emotional insensitivity but increasing stress assessed by cortisol. Second, ketamine had an effect on altering brain connectivity, particularly for specific connections between regions of the reward and negative affect circuits and involving thalamic sub-regions. Third, regarding brain-response associations, ketamine-induced increases in amygdala-anteroventral thalamus coupling were correlated with greater dissociation and intoxication, whereas decreases in the coupling of the anteromedial thalamus and posterior parietal thalamus were correlated with increased sensory aspects of reward responsiveness. Additional specific correlations were observed between affective measures relevant to reward responsiveness or its absence and drug-altered changes in localized functional connections involving the nucleus accumbens (NAcc), amygdala, and thalamic sub-regions. We also discovered a consistent profile of negative associations between ketamine altered connectivity involving the NAcc and specific thalamic sub-regions and effects of anxiety. Further, drug-altered increases in the coupling of the amygdala and anteroventral thalamus were associated with increases in cortisol, an indicator of biochemical stress. The findings highlight the utility of integrating self-reports, objective measures, and functional neuroimaging to disentangle the brain states underlying specific acute responses induced by ketamine. With the likely continued expansion of FDA indications for ketamine, understanding acute responses and underlying neural mechanisms is important for maximizing the therapeutic potential of ketamine while minimizing the risk of promoting misuse or abuse of this substance.

neuroscience↗

bioRxiv2021

Parallel valence processing alterations associated with compulsive behavior in SAPAP3 knockout mice and human OCD

Abnormalities in valence processing - the processing of aversive or appetitive stimuli - may be an underrecognized component of obsessive-compulsive disorder (OCD). Independent experimental paradigms have suggested disturbance of emotional valence systems in OCD, yet no standardized assay has been employed to assess both negative and positive valence processing in clinical studies of OCD patients, either at baseline or in response to therapeutic interventions. Additionally, preclinical rodent models are critical for treatment discovery in OCD, yet investigations examining whether rodent models of compulsive behavior similarly show alterations in valence systems have been limited. We sought to establish paradigms for assessing valence processing across both human OCD patients and in a preclinical rodent model: in OCD patients, we used validated behavioral tests to assess explicit and implicit processing of fear-related facial expressions (negative valence) and socially-rewarding happy expressions (positive valence); in the SAPAP3 knockout (KO) mouse model of compulsive behavior, we used auditory fear conditioning and extinction (negative valence) and reward-based operant conditioning (positive valence). We find that OCD patients show enhanced negative and impaired positive valence processing, and that performance on valence processing tasks correlates with clinical measures of OCD severity. We further find that SAPAP3 KO mice show heightened negative and impaired positive valence processing alterations similar to those of OCD patients. Our results show parallel valence processing abnormalities in OCD patients and a preclinical rodent model of compulsive behavior, and suggest valence processing alterations as novel therapeutic targets across a translational research spectrum.

neuroscience↗

bioRxiv2021

Diversification of Transcription Factor NF-κB in Protists

In this report, we investigate the evolution of transcription factor NF-{kappa}B by examining its structure, activity, and regulation in two protists using phylogenetic, cellular, and biochemical techniques. In Capsaspora owczarzaki (Co), we find that full-length NF-{kappa}B has an N-terminal DNA-binding domain and a C-terminal Ankyrin (ANK) repeat inhibitory domain, and its DNA-binding activity is more similar to metazoan NF-{kappa}B rather than Rel proteins. As with mammalian NF-{kappa}B proteins, removal of the ANK repeats is required for Co-NF-{kappa}B to enter the nucleus, bind DNA, and activate transcription. However, C-terminal processing of Co-NF-{kappa}B is not induced by co-expression of IKK in human cells. Exogenously expressed Co-NF-{kappa}B localizes to the nucleus in Co cells. NF-{kappa}B mRNA and DNA-binding levels differ across three life stages of Capsaspora, suggesting distinct roles for NF-{kappa}B in these life stages. RNA-seq and GO analyses identify possible gene targets and biological functions of Co-NF-{kappa}B. We also show that three NF-{kappa}B-like proteins from the choanoflagellate Acanthoeca spectabilis (As) all consist of primarily the N-terminal conserved Rel Homology domain sequences of NF-{kappa}B, and lack C-terminal ANK repeats. All three As-NF-{kappa}B proteins constitutively enter the nucleus of human and Co cells, but differ in their DNA-binding and transcriptional activation activities. Furthermore, all three As-NF-{kappa}B proteins can form heterodimers, indicating that NF-{kappa}B diversified into multi-subunit families at least two times during evolution. Overall, these results present the first functional characterization of NF-{kappa}B in a taxonomic kingdom other than Animalia and provide information about the evolution and diversification of this biologically important transcription factor. SignificanceThese results represent the first functional characterization of the biologically important transcription factor NF-{kappa}B in a taxonomic kingdom other than Animalia. As such, they provide information on the evolutionary origins and basal diversification of NF-{kappa}B outside of metazoans. These results suggest that NF-{kappa}B plays life stage-specific roles in Capsaspora, the closest unicellular ancestor to all metazoans. Finally, the analysis of three NF-{kappa}B proteins in a single choanoflagellate indicates that choanoflagellates have subclasses of NF-{kappa}Bs, which can form heterodimers, suggesting that NF-{kappa}B subunit expansion and diversification has occurred at least twice in evolution.

cell biology↗

bioRxiv2020

No support for white matter microstructural properties and connectivity differences in the combined and inattentive adhd presentations.

Evidence from functional neuroimaging studies support neural differences between the Attention Deficit Hyperactivity Disorder (ADHD) presentation types. It remains unclear if these neural deficits also manifest at the structural level. We have previously shown that the ADHD combined, and ADHD inattentive types demonstrate differences in graph properties of structural covariance suggesting an underlying difference in neuroanatomical organization. The goal of this study was to examine and validate white matter brain organization between the two subtypes using both scalar and connectivity measures of brain white matter. We used both tract-based spatial statistical (TBSS) and tractography analyses with network-based Statistics (NBS) and graph-theoretical analyses in a cohort of 35 ADHD participants (aged 8-17 years) defined using DSM-IV criteria as combined (ADHD-C) type (n=19) or as predominantly inattentive (ADHD-I) type (n=16), and 28 matched neurotypical controls. We performed TBSS analyses on scalar measures of fractional anisotropy (FA), mean (MD), radial (RD), and axial (AD) diffusivity to assess differences in WM between ADHD types and controls. NBS and graph theoretical analysis of whole brain inter-regional tractography examined connectomic differences and brain network organization, respectively. None of the scalar measures significantly differed between ADHD types or relative to controls. Similarly, there were no tractography connectivity differences between the two subtypes and relative to controls using NBS. Global and regional graph measures were also similar between the groups. A single significant finding was observed for nodal degree between the ADHD-C and controls, in the right insula (corrected p=.029). Our result of no white matter differences between the subtypes is consistent with most previous findings. These findings together might suggest that the white matter structural architecture is largely similar between the DSM-based ADHD presentations.

neuroscience↗

bioRxiv2019

α1A-adrenoceptor inverse agonists and agonists modulate receptor signalling through a conformational selection mechanism

G-Protein Coupled Receptors (GPCRs) transmit signals across the cell membrane via an allosteric network from the ligand-binding site to the G-protein binding site via a series of conserved microswitches. Crystal structures of GPCRs provide snapshots of inactive and active states, but poorly describe the conformational dynamics of the allosteric network that underlies GPCR activation. Here we analyse the correlation between ligand binding and receptor conformation of the 1A-adrenoceptor, known for stimulating smooth muscle contraction in response to binding noradrenaline. NMR of 13C{varepsilon}H3-methionine labelled 1A-adrenoreceptor mutants, each exhibiting differing signalling capacities, revealed how different classes of ligands modulate receptor conformational equilibria. 13C{varepsilon}H3-methionine residues near the microswitches revealed distinct states that correlated with ligand efficacies, supporting a conformational selection mechanism. We propose that allosteric coupling between the microswitches controls receptor conformation and underlies the mechanism of ligand modulation of GPCR signalling in cells.

biochemistry↗

bioRxiv2019

Short-term test-retest reliability of the human intrinsic functional connectome

Functional connectivity is frequently used to quantify the complex synchronous distributed fluctuations in neuronal activity derived from functional Magnetic Resonance Imaging and to generate network representations of human brain function. Such \"functional connectomes\" have great promise for mechanistic studies and for clinical translation. However, we do not know to what extent a functional connectome is stable over time for an individual. In the present work, we evaluate the short-term test-retest reliability of functional connectomes in a large publicly available sample of healthy participants (N=833) scanned on two consecutive days. We also assess the consequences on reliability of three methodological procedures for which a clear guideline in the community is lacking: atlas choice, global signal regression and thresholding. By adopting the intraclass correlation coefficient as a reliability metric, we demonstrate that a relatively small portion of the intrinsic functional connectome is characterized by good (4-6%) to excellent (0.08-1%) stability over time. In particular, connectivity between prefrontal, parietal and temporal areas appears to be especially stable over short timescales. Also, while unreliable edges of the functional connectome are generally weak in terms of average functional connectivity, reliable edges are not necessarily strong. Methodologically, we demonstrate that multimodal parcellation and averaging of connections within known networks are practices that improve reliability. Harnessing this knowledge, for example by honing in on the reliable portion of the connectome, offers one way forward for studies of trait-like features within the normative connectome and for discovery of biomarkers in clinical cohorts.

neuroscience↗

bioRxiv2019

Transcription factor NF-κB in a basal metazoan, the sponge, has conserved and unique sequences, activities, and regulation

Biological and biochemical functions of immunity transcription factor NF-{kappa}B in basal metazoans are largely unknown. Herein, we characterize transcription factor NF-{kappa}B from the demosponge Amphimedon queenslandica (Aq), in the phylum Porifera. Structurally and phylogenetically, the Aq-NF-{kappa}B protein is most similar to NF-{kappa}B p100 and p105 among vertebrate proteins, with an N-terminal DNA-binding/dimerization domain, a C-terminal Ankyrin (ANK) repeat domain, and a DNA binding-site profile more similar to human NF-{kappa}B proteins than Rel proteins. Aq-NF-{kappa}B also resembles the mammalian NF-{kappa}B protein p100 in that C-terminal truncation results in translocation of Aq-NF-{kappa}B to the nucleus and increases its transcriptional activation activity. Overexpression of a human or sea anemone I{kappa}B kinase (IKK) can induce C-terminal processing of Aq-NF-{kappa}B in vivo, and this processing requires C-terminal serine residues in Aq-NF-{kappa}B. Unlike human NF-{kappa}B p100, however, the C-terminal sequences of Aq-NF-{kappa}B do not effectively inhibit its DNA-binding activity when expressed in human cells. Tissue of another demosponge, a black encrusting sponge, contains NF-{kappa}B site DNA-binding activity and an NF-{kappa}B protein that appears mostly processed and in the nucleus of cells. NF-{kappa}B DNA-binding activity and processing is increased by treatment of sponge tissue with LPS. By transcriptomic analysis of A. queenslandica we identified likely homologs to many upstream NF-{kappa}B pathway components. These results present a functional characterization of the most ancient metazoan NF-{kappa}B protein to date, and show that many characteristics of mammalian NF-{kappa}B are conserved in sponge NF-{kappa}B, but the mechanism by which NF-{kappa}B functions and is regulated in the sponge may be somewhat different.

cell biology↗